This invention relates to a method for the treatment of infectious diseases in man and animals. In particular, it relates to a method for the treatment of bacterial infections in man and animals which comprises administering by the oral route certain heteroarylacylamido-3-chloro-substituted cephalosporins. Also provided are pharmaceutical formulations for oral therapy and 3-halo-substituted cephalosporins useful in the peroral treatment method.
Since the discovery of cephalosporin C by E. P. Abraham, a wide variety of structurally distinct cephalosporin antibiotics have been prepared and evaluated. A number of these broad spectrum cephalosporins have achieved clinical importance among which are cephalothin, cephaloridine, cefazolin, cephamandole, cefoxitin, cephapirin, ceftazidime, cefotaxime, cefuroxime, cephalexin, and cefaclor.
The cephalosporin antibiotics as a class, with the exceptions noted below, are generally recognized as being poorly absorbed from the gastrointestinal tract and, accordingly, are administered parenterally. Despite the wide variety of structurally distinct cephalosporins that have been prepared and evaluated, little is known regarding the structural features required to imbue a cephalosporin with the property of ready absorption from the gastrointestinal tract.
The exceptions to the above are represented by the antibiotics cephalexin, cefaclor, and cephradine. These antibiotics exhibit high absorption from the gastrointestinal tract and thus are effective when taken orally. Structurally, these antibiotics have either the phenylglycyl group or the structurally similar 1,4-cyclohexadienylglycyl group as the 7-position side chain. Likewise, other cephalosporins having such an arylglycyl group in the 7-position are shown to exhibit absorption by the oral route. Consequently, it has become generally recognized that a structural feature required for high oral absorption is an arylglycyl 7-position side chain or a close analog thereof.
Chauvette describes in U.S. Pat. No. 4,064,343, 3-chloro-7.beta.-acylamido-3-cephem-4-carboxylic acid compounds as antibiotics. In column 25 of the patent, Chauvette teaches the parenteral administration, i.e., subcutaneously or intramuscularly, of these non-arylglycyl substituted compounds. In contrast, in U.S. Pat. No. 3,925,372, Chauvette describes cefaclor and related compounds and their effectiveness when administered orally. Structurally, cefaclor contains the D-phenylglycyl group, an arylglycyl moiety, as the side chain in the 7-position of the cephem nucleus.
The present invention comprises the discovery that certain 3-chloro-substituted cephalosporins having a non-arylglycyl side chain demonstrate surprising peroral bioavailability.